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Pathway-based Rare Variant Burden Analysis Identifies a Role for the Complement System in an Extreme Phenotype of Sepsis with Coagulopathy [article]

Pavan K. Bendapudi, Sumaiya Nazeen, Justine Ryu, Onuralp Soylemez, Betty Rouaisnel, Meaghan Colling, Bryce Pasko, Alissa Robbins, Michael Bouzinier, Lindsay Tomczak, Lindsay Collier, Sanjay Ram (+10 others)
2022 medRxiv   pre-print

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https://web.archive.org/web/20220424020758/https://www.medrxiv.org/content/medrxiv/early/2022/02/25/2022.02.24.22271459.full.pdf

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Extreme disease phenotypes have the potential to provide key pathophysiologic insights, but the study of these conditions is challenging due to their rarity and the limited statistical power of existing methods. Herein, we apply a novel pathway-based approach to investigate the role of rare genomic variants in infectious purpura fulminans (PF), an extreme phenotype of sepsis with hyperinflammation and coagulopathy for which the role of inherited risk factors is currently unknown. Using whole
more » ... me sequencing, we found a significantly increased burden of rare, putatively function-altering coding variants in the complement system in patients with PF compared to unselected patients with sepsis (p-value = 0.01). Functional characterization of a subset of PF-associated variants in integrin complement receptors 3 and 4 (CR3 and CR4) revealed that they exhibit a pro-inflammatory phenotype. Our results suggest that rare inherited defects in the complement system predispose individuals to the maladaptive hyperinflammatory response that characterizes severe sepsis.
doi:10.1101/2022.02.24.22271459 fatcat:ri6elmh3nfa6zi6wjvz3hqjbja
Citation

Pavan K. Bendapudi, Sumaiya Nazeen, Justine Ryu, Onuralp Soylemez, Betty Rouaisnel, Meaghan Colling, Bryce Pasko, Alissa Robbins, Michael Bouzinier, Lindsay Tomczak, Lindsay Collier, Sanjay Ram, Agnes Toth-Petroczy, Joel Krier, Elizabeth Fieg, Walter H. Dzik, James C. Hudspeth, Olga Pozdnyakova, Valentina Nardi, Richard Maas, Shamil Sunyaev, Julie-Aurore Losman. "Pathway-based Rare Variant Burden Analysis Identifies a Role for the Complement System in an Extreme Phenotype of Sepsis with Coagulopathy." medRxiv (2022)